2-(3-benzo(b)thenyl)-2-thiopseudourea and its pharmaceutically acceptable salts

ABSTRACT

2-(3-BENZO(B)THENYL)-2-THIOPSEUDOUREA AND ITS PHARMAEUTICALLY ACCEPTABLE SALTS ARE A NEW GROUP OF COMPOUNDS WHICH ARE USEFUL AS ANTI-AGGRESSION AGENTS.

United States Patent s 790 600 zs BENZOMTHENSKL) i z THIOPSEUDOUREA ANDITS PHARMACEUTICALLY ACCEPTABLE SALTS Zaven S. Ariyan, Woodbury, Conn.,and Shih-Yu Ma, Wayne, N.J., assignors to Uniroyal, Inc., New York,

Nb brawing. Filed Apr. 6, 1972, Ser. No. 241,837 rm. c1. A61k 27/00;001a 63/22 U.S. Cl. 260330.5 2 Claims ABSTRACT OF THE DISCLOSURE2-(3-benzo [b]thenyl)-2-thiopseudourea and its pharmaceuticallyacceptable salts are a new group of compounds which are useful asanti-aggression agents.

FIELD OF THE INVENTION pseudourea CH2 S |3=NH NHr s:

and its pharmaceutically acceptable salts-novel compounds which havebeen found to be highly selective for the abolition of aggressivebehavior at doses which cause little or no signs or symptoms of centralnervous system depression or toxicity. The pharmaceutically acceptablesalts which have been tested, all of which appeared to have the activitymentioned above, include the chloride, bromide, benzoate, iodide,p-toluenesulfinate, p-toluenesulfonate and acetate. It is thought that,when taken orally, the salts may be buffered and the hydroxide or freebase formed. On the other hand, the acid pH of the stomach (around 2 inhumans) due to the presence of HCl is believed to cause reversion to thechloride, S-3-benzo- [b]thenylisothiuronium chloride,

Therefore, much of the discussion of the invention hereinafter will bewith reference to the chloride. However, it will be understood that theinvention also encompasses the free base and other pharmaceuticallyacceptable salts thereof. In addition to the salts mentioned above,other suitable salts include the sulfate, nitrate, phosphate, maleate,fumarate, succinate, tartrate and citrate. Thus, While not wishing to bebound to any theory of how the compounds of the invention act in vivo,it is also believed possible that the base is the pharmaceuticallyactive compound that is formed from the salts in animal tissue fluid.

It is well accepted in neuropharmacology that there is no cleardistinction between sedative-hypnotics and minor tranquilizers. Allknown minor tranquilizers which are effective in reducing anxiety alsoproduce dowsiness, ataxia (inability to coordinate muscular movements)and sleep when given in larger doses. All sedative-hypnotic drugs insmall doses are anxiolytic (causing apprehension or anxiety). Sedativehypnotics such as alcohol and Ice short-acting barbiturates tend toproduce behavioral excitation prior to promoting drowsiness and sleep.The sedative-hypnotics and minor tranquilizers produce discrete,predictable changes of behavior that can be applied to therapeuticadvantage in neurotics. Aside from their ability to promote sleep, theirmajor behavioral actions of therapeutic advantage are their abilities toslightly reduce the level of arousal-excitability, overcome passiveavoidance (social withdrawl, suppressed or submissive) behavior,slightly diminish aggressive hostility, and increase the response toenvironmental stimuli. The effect, for example, of a psychomimetic(inducing psychosislike symptoms) drug on animal behavior, such as LSDin rats and cats, has been said to increase excitement and aggression.

Currently, aggressive behavior in mental disease patients is usuallycontrolled by such major tranquilizers as chlorpromazine. This approachto the problem of controlling mental disorders is not entirelysatisfactory since patients under the influence of this type ofmedication are overtly depressed and not able to return satisfactorilyto society and to function normally. Chlorpromazine is a strong centralnervous system depressant, both in normal and schizophrenic patients.Its most salient feature, however, is the ability to inhibit aggressivebehavior in abnsive and destructive schizophrenics. It has been the drugof choice for the treatment of so-called back ward schizophrenics, andis now used in out-patient therapy in cases of simple schizophrenia. Thecompound has many side-effects, the most serious of which is that itcauses depression at the same time that it alleviates the schizophrenicsymptoms. Incidentally, it also has a disadvantage in that it is quitetoxic and has caused liver damage and blood disorders.

The abolition of aggressive behavior in schizophrenics withoutneurotoxicity as characterized by depression would be a most desirablefeature for a new drug in the therapy of mental disease. The compoundsof the present invention have been found to be agents which selectivelyblock aggressive behavior but do not cause depression.

Accordingly, in one aspect thereof, the invention is a method oftreating aggressive behavior. In another aspect, the invention is thecompound 2-(3-benzo[b]thenyl)-2- thiopseudourea and its pharmaceuticallyacceptable salts, and pharmaceutical compositions comprising thesecompounds. A particularly preferred compound of the present invention isS-3-benzo[b] thenylisothiuronium chloride.

DESCRIPTION OF THE PRIOR ART The patent literature discloses manybiologically active benzo[b]thiophene compounds but does not disclosethe particular compounds of the present invention nor suggest the hereindisclosed properties thereof. For example, U.S. Pat. No. 2,916,495 toEdgerton discloses a class of betathianaphthenylalkyl hydrazines ashaving advantageous hypotensive activity and the like; U.S. Pat. No.3,010,971 teaches that certain 2-(benzo-[b]-thenyl) cyclopropylaminederivatives have the ability to act as anti-depressive, ataractic andhypotensive agents; British Pat. Nos. 855,115 and 1,174,411 and U.S.Pat. No. 3,070,606 disclose a number of benzo[b]thiophene derivatives ashaving several pharmaceutical applications; and German patentpublication No. 1,937,514 (Feb. 19, 1970) disclosesbenzo[b]thiophenecarboxamides as being effective on the central nervoussystem, for example as having antiemetic action agaist morphine orapomorphine. Moreover, U.S. Pat. No. 3,186,990 contains a genericdisclosure which encompasses S2-benzo[b]thenyl isothiuronium chloride,the Z-isomer of the chloride compound of the present invention, andteaches that the class of compounds to which it relates are useful asfungicides. A similar disclosure is present in British Pat. No. 889,002.

3 In French Pat. 2,068,420, issued Aug. 27, 1971, 1-(benzo-[b]-3-thienyl-methyl) quanidine,

and its pharmaceutically acceptable salts, compounds which arestructurally closely related to those of the present invention, aredisclosed as being useful in the treatment of hypertension (higharterial blood pressure), hyperthyreosis (excessive functional activityof the thyroid gland) and tachycardia (relatively rapid heart action).It will be noted that the compounds of the French patent diflfer fromthose of the present invention by having an -NH radical substituted foran S- radical between the -CH and the on the side chain. However, as isknown, particularly in the pharmaceutical field, this difference is morethan enough to result in unanticipatable diiferences in properties.Indeed, such differences appear to exist in the present case. Thus,although both groups of compounds are pharmaceuticals, their utilitiesare in markedly different and substantially unrelated pharmaceuticalapplications.

In addition, two U.S. patents, Nos. 3,033,975 and 3,041,351, whichrelate to flavoring agents, contain identical descriptions of thepreparation of 3-thionapl1thylmethyl mercaptans. (Examples 3 and 2 ofthese patents, respectively.) As will become apparent from thedescription hereinafter of the preparation of the chloride compound ofthe present invention, the synthesis described in these two patents,more particularly at column 2, lines 1- 18 of US. Pat. No. 3,041,351 andcolumn 3, lines 35- 43 of US. Pat. No. 3,033,875, follows a proceduresimilar to that described herein. However, the patentees reacted theresulting intermediate with NaOI-I; and they neither appreciated,identified nor isolated the intermediate. Moreover, they teach aprocedure whereby the intermediate is destroyed by treatment withaqueous sodium hydroxide.

SUMMARY OF THE INVENTION The present invention provides a method ofcontrolling aggressive behavior in an animal subject without causing thecentral nervous system depression which is a typical side effect ofdrugs heretofore used to treat aggressive behavior. This is achieved byadministering to an animal subject a therapeutically effective amount ofa compound selected from the group consisting of 2-(3-benzo{b] thenyl)-2-thiopseudourea and its pharmaceutically acceptable salts, preferablyS-3-benzo[b]thenyl isothiuronium chloride. Generally, the amountadministered will be from about 1 to 50 mg./kg./ day of body weight,preferably from about 2 to 8 mg./kg./day.

The invention further provides as new compositions of matter,2-(3-benzo[b]theny1)-2-thiopseudourea CHrS C\ NH: s

wherein Z is an anion derived from an acid which is pharmaceuticallyacceptable and whose pK value is between 0.4 and 6.5 and n is an integerfrom 1 to 3 equal to the charge on the anion. As indicated, the chloride(Z is Cl"- and n is 1) is a particularly preferred salt.

The pharmaceutical compositions of the present invention comprise, incombination, a therapeutically eifective amount of a compound of thepresent invention and a pharmaoeutically acceptable carrier or diluenttherefor.

For example, in the case of a tablet, the composition will comprise, inaddition to the active ingredient, fillers, binders and diluents such aslactose, methylcellulose, talc, gum tragacanth, gum acacia, agar,polyvinylpyrrolidone, stearic acid and/or corn starch. In the case of aliquid suspension for oral administration, the composition willcomprise, in addition to the active ingredients, a filler such as sodiumcarboxyrnethylcellulose and/or a syrup, e.g. a glycerine based syrup. Inthe case of a parenteral solution or suspension, the composition willcomprise, in addition to the active ingredient, a suitable liquidsolvent or dispersant such as a saline solution.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of the presentinvention may be obtained by conventional methods. Thus,S-3-benzo[b]thenyl isothiuronium chloride (A), is obtained from thereaction of 3-chloromethylbenzo[b]thiophene (C) with an excess ofthiourea in a water-free organic solvent which is a solvent forthiourea. Absolute ethanol is the preferred solvent. Other suitablesolvents include dioxane, acetonitrile and dimethyldiethylene glycol(isothiuronium chlorides,

in general, hydrolyze easily in aqueous solution).

-Grnso NHg s (Trainer S j The starting reactant (C) was obtained fromthe chloromethylation of benzo [b]thiophene. The other salts areobtained analogously. The free base, 2-(3-benzo[b]thenyl)-Z-thiopseudourea was obtained from the chloride by treat ment with anaqueous sodium bicarbonate solution as follows:

aqueous NaHCOa NH:+ cnisoi Q omen 1 NH: (A) (D) The hydrolysis ofS-Z-benzo [b]thenyl isothiuronium chloride (B) yielded 2-benzo[b]thenylmercaptan (E), along with a small amount of 2-benzo[b]thenyl disulfide(F).

// C1 LOH" 2.H S CH2SC\ S CHzSH The disulfide (F) is believed to be theproduct of the autoxidation of the mercaptan (E).

1. n-BuLi 2. C02

EXAMPLE 1 (A) Preparation of 3-chloromethylbenzo[b]thiophene Amodification of the procedure reported by Blicke and Sheets [F. F.Blicke and Don G. Sheets, J. Am. Chem. Soc. 70 3768 (1948)] was used forthe preparation of 3- chloromethylbenzo [b]thiophene by reactingbenzo[b] thiophene with formaldehyde in an excess of concentratedhydrochloric acid as follows:

805 g. (5.65 moles) of benzo[b1thiophene were added dropwise to astirred mixture of 3600 ml. of concentrated aqueous hydrochloric acidand 540 ml. of a 40% aqueous formalin solution at a temperature of about5 C. over a period of 3 hours. After stirring for 1 hour, the resultingpinkish mixture was heated to and held at 65 C. for 1 hour. Then thelower organic layer was separated. The aqueous layer was extracted withfour 800 ml. portions of benzene. The organic layer and the benzeneextracts were combined and then dried by passing through anhydrouspotassium carbonate and hydrous sodium sulfate. Evaporation andfractional distillation through a Vigreux column afforded 831.7 g.(75.3%) of 3-chloromethylbenzo[b] thiophene, B.P. 120-l32 C. (0.7-1.9mm.), 11 1.6440. [Lit. B.P. 125-127 C. (2.0 mm.)].

(B) Preparation of S-3-benzo[b]thenyl isothiuronium chloride S-3-benzo[b]thenyl isothiuronium chloride was prepared by the reaction of3-chloromethylbenzo[b]thiophene with an excess of thiourea in absoluteethanol as follows:

A sample of 91 g. (1.2 moles) of thiourea in 1500 ml. of absoluteethanol was heated to a temperature of 70 C. to obtain a clear solution.Then 109.9 g. (0.6 mole) of 3-chloromethylbenzo[b]thiophene were addeddropwise over a period of 15 minutes. The reaction mixture was thenheated under refluxing (83 C.) for 2 hours. On cooling to an ambienttemperature of about 22 C. by stirring for about 30 minutes, a colorlesssolid weighing g. (84.5% yield) was deposited. It had a melting point of213-217 C. Recrystallization from absolute ethanol atforded a colorlesscrystalline solid: M.P. 222.5-224.5 C. (dec.); IR,

max.

3160 cm. (broad), 2720 cmf 1630 cmr' 755 cmfi N.M.R.

DMSO du TMS (C) Hydrolysis of S-3-benzo[b] thenyl isothiuronium chlorideIn order to further characterize the structure of S-3- benzo[b] thenylisothiuronium chloride, it was hydrolyzed in the presence of sodiumhydroxide to yield 2-benzo [b] thenyl mercaptan as follows:

52 g. (0.2 mole) of S-3-benzo[b]thenyl isothiuronium chloride were addedto a solution of 28.6 g. of sodium hydroxide in 430 ml. of distilledwater at 45 C. The resulting mixture was then heated while stirring to99 C. and held at 99 C. for 4 /2 hours, giving a clear yellow solution.On cooling to 15 C. (about 30 minutes), the solution was acidified withconcentrated aqueous hydrochloric acid. An organic layer was therebyformed and was then separated. The aqueous residue was extracted with700 ml. of ether in three portions. The organic layer and the etherextracts were combined and dried over anhydrous sodium sulfate.Evaporation and fractional distillation yielded 30.2 g. (83.8%) of acolorless liquid product, 3-thionaphthylmethyl mercaptan, which wascharacterized as follows: B.P. 104-109 C. (0.25-0.28 mm. Hg), n 1.6733[Lit. (U.S. Pat. 3,041,351 and Chemical Abstracts 57 13729 [1962]) B.P.156 C. (9.5 mm.)]; N.M.R.

0014 TMS 1.54 (SH, triplet, J=7 caps), 3.72 (CH2-, doublet, J=7 cps.),7.07 (Hz, singlet), 7.19 (H5+H6, multiplet), 7.61 (Hm-H multiplet).

EXAMPLE 2 Preparation of 2-(3-benzo [b]thenyl(-2-thiopseudourea Asuspension of 0.6 g. of S-3-benzo[b]thenyl isothiuronium chloride in 15ml. of water was chilled in an ice water bath. A 10% aqueous sodiumbicarbonate solution was added dropwise until the pH of the solution wasabove 8. The insoluble product, weighing 0.57 g., was collected,dissolved in 8.0 ml. of ethyl acetate at 25 C. and filtered to removeinsoluble impurities. Upon cooling in an ice water bath, the 2 (3 benzo[b]thenyl)-2-thiopseudourea product precipitated out of solution as awhite solid. The yield was 0.4 g. of a product having a melting point of105-107 C. It was characterized as follows: IR,

3400, 1620, 1580, 77s cm.- ;N.M.R.

DMSO d TMS 3benzo[b]thenyl mercaptan The decomposed sample has a meltingrange of 110 to 203 C. presumably because of the presence ofdicyandiamide (M.P. 212 C.), which forms when cyanamide dimerizes.

eyanamide EXAMPLE 3 (A) Preparation of S-2-benzo[b]thenyl isothiuroniumchloride As described below, a sample of S-2-benzo[b]thenylisothiuronium chloride was made by the reaction of2-chloromethylbenzo[b]thiophene with thiourea. The starting 2-chloromethylbenzoflfl thiophene was prepared via the known intermediatesbenzo [b]thiophene-2-carboxylic acid and2-hydroxymethyl-benzoEb]thiophene as herein above outlined schematicallybefore Example 1.

A yellow solution of 18.3 g. (0.1 mole) of2-chloromethylbenzo[b]thiophene in 70 ml. of benzene was added dropwiseover a period of 80 minutes to a sample of 15.2 g. (0.2 mole) ofthiourea in a mixed solvent of 150 m1. of absolute ethanol and 100 ml.of benzene. An exotherm from 25 C. to 28 C. occurred.

The reaction mixture was then refluxed for 2 hours. Evaporation yieldeda wet, yellow, solid residue. After stirring with 100 ml. of petroleumether for about 15 minutes, filtration yielded 34 g. of a light yellowsolid product having a melting point of 140-156" C. A sample of 25.7 g.of the crude reaction product was stirred at room temperature with 230ml. of acetonitrile in two portions to yield 14.6 g. of a pale yellowsolid having a melting point of 184l88 C. An analytical sample having amelting point of 194-l96 C. was prepared by dissolving 0.55 g. of thisproduct in 75 ml. of water at 65 C., filtering and reprecipitating withconcentrated aqueous hydrochloric acid. The product, S-2-benzo[b] thenylisothiuronium chloride, was characterized as follows: IR,

3150 cm." (broad), 2720 cmr- 1650 cm.- 750 cmi' N.M.R.

DMSo-da TMs 4.98 (CH S, singlet), 7.34 (H H-H multiplet), 7.48 (Hsinglet), 7.85 (H +H multiplet), 9.45 (ZNH broad singlet).

Analysis.Calcd for C H N S CI (percent): C, 46.46; H, 4.28, N, 10.83; S,24.78; Cl, 13.70. Found (per- 8 cent): C, 46.49, 46.28; H, 4.43, 4.52;N, 10.30, 10.28; S, 22.40, 26.93; Cl, 13.48, 13.86.

(B) Hydrolysis of S-2-benzo[-b]thenyl isothiuronium chloride In order todilferentiate between the corresponding 2- and 3-S-benzo[-b]thenylisotbiuronium chloride isomers, S 2 bemzo[b]theny1 isothiuroniumchloride was hydrolyzed to 2-benzo[b]thenyl mercaptan, a solid product,as follows: 14.6 g. (0.057 mole) of 2-benzo[b]thenyl isothiuroniumchloride were added to a solution of 6.4 g. of sodium hydroxide in ml.of water having a temperature of 25 C. An exotherm to 34 C. occurred.After 15 minutes, the reaction mixture was then heated to and held at 98C. for 4% hours, giving a yellow solution containing some insolublematerial. This solution was then diluted with 200 ml. of water, cooledto a temperature of 15 C. with an ice water bath and acidified withconcentrated aqueous hydrochloric acid. The aqueous solution was thenextracted with 1000 ml. of benzene in four portions. The yellow benzeneextract was washed with water and saturated sodium chloride solution,and then dried over anhydrous sodium sulfate. Evaporation yielded 9.5 g.(100% yield) of a yellow, wet, solid product.

A sample of 4.0 g. of this crude product was chromatographed on silicagel (230 g.), using a cyclohexane-benzene mixture (4:1 for elution.Evaporation of the first main fraction yielded 1.06 g. of pale yellowcrystalline plates of 2benzo[- b]thenyl mercaptan, which had thefollowing characteristics: Melting point, 505l C. (from cyclohexane);IR,

Neat men.

2550 cmr 740 cmr N.M.R.

0 C14 TMS use 480 cmr N.M.R.

01301, TMS

3.97 (-CH singlet), 7.10 (H singlet), 7.29

(H +H multiplet), 7.73 (H +H-;, multiplet).

Analysis.Calcd for C H S (percent): C, 60.30; H, 3.94; S, 35.77. Found(percent): C, 60.06, 60.04; H, 3.96, 4.00; S, 34.70, 34.39.

The chemical evidence, physical data and biological activity of both 3-and 2-S-benzo[b]thenyl isothiuronium chloride, which are summarizedbelow, show that the structure of the chloride compound of thisinvention is the 3-isomer of 'S-benzo[b]thenyl isothiuronium chloride:

S-S-benzo [b] thenyl isothiuronium chloride Melting point: 222-224 C.

Mixed melting point with Z-isomer: -l9l C.

Infrared spectrum: similar to that of the 2-isomer.

N.M.R. spectrum: For H 8 7.90 (see Table I).

Hydrolysis product: 3-benzo[b]thenyl mercaptan, a liquid; boiling point104-l09 C. (0.28-0.25 mm); n 1.6733, N.M.R. (see Table II) for H o'=7.07singlet; SH, tr=1.54 triplet.

Biological activity: Active as an antiaggression drug.

9 S-2-benzo[b]thenyl isothiuronium chloride M.P.: 194-196 C.

Mixed M.P. with 3-isomer: 165-191" C.

Infrared spectrum: similar to that of the 3-isomer.

N.M.R. spectrum: For H 6 7.48 (see Table I).

Hydrolysis product: 2-benzo[b]thenyl mercaptan, a solid, M.P.: 50-51 C.N.M.R. (see Table II) for H o'=7.08 singlet; AH, o-=1.81 triplet.

Biological activity: Inactive as an antiaggression drug.

TABLE I N.M.R. spectral properties of 3- and 2-S-benzolb1thenylisothiuronium chloride Chemical Shift in, ppm.

N.M.R. spectral properties 013- and 2-benzo[b]thenyl mercaptan Chemicalshift in, p.p.m.

3-isomer 1. 54 3. 72 7. 07 7. 19 7. 6].

EXAMPLE 4 (A) Preparation of 3-bromomethylbenzo[b]thiophene To a stirredmixture of 400 ml. of 40% aqueous hydrobromic acid and 60 ml. of 40%aqueous formaldehyde at 6 C. were added, dropwise, 80 g. (0.6 mole) ofbenzo- [b]thiophene over a period of 20 minutes. After stirring for 1hour, the reaction mixture was heated and held at 65 C. for one hour andthen chilled to 15 C., followed by the addition of 500 ml. of ice water,and then extracted with 900 m1. of benzene in three portions. Theextracts were combined and dried by passing through anhydrous potassiumcarbonate and anhydrous sodium sulfate. Evaporation on a steam bathyielded 136 g. of a dark brown crude liquid product. Fractionaldistillation removed 9.5 g. of low-boiling material. The higher boilingresidue, 3-bromomethylbenzo[b]thiophene, weighed 95 g. (70% yield).

(B) Preparation of S-3-benzo[b]thenyl isothiuronium bromide 95 g. of the3-bromomethylbenzo [bJthiophene prepared above was suspended in 200 ml.of absolute ethanol and added to a refluxing solution (80 C.) of 64 g.(0.84 mole) of thiourea in 600 ml. of absolute ethanol. Reflux wascontinued for two hours, and the resultant dark brown solution was thenallowed to cool to room temperature and filtered to remove a traceamount of insoluble material. Evaporation of the filtrate yielded 122.4g. of a pale yellow solid product, M.P. 138-168 C. Trituration of thecrude product in 125 ml. of acetone yielded 65 g. (51% yield) of theproduct, S-3-benzo[b]thenylisothiuronium bromide, M.P. 205-210 C. Ananalytical sample, M.P. 207-209 C., was prepared by dissolving 1.0 g. ofthe product in 25 ml. of absolute ethanol and 1.0 ml. of water andreprecipitating with the addition of 40% aqueous hydrobromic acid. Itwas characterized as follows: IR,

cent): C, 38.76, 39.01; H, 3.79, 3.79; Br, 24.60, 24.58; N, 8.71, 8.83;S, 20.3, 20.1.

10 EXAMPLE 5 Preparation of S-3-benzo[b]thenyl isothiuronium iodide Amixture of 12.9 g. (0.05 mole) of S-3-benzo[b] thenyl isothiuroniumchloride and 45 g. (0.3 mole) of sodium iodide in 1000 m1. of acetonewas heated under reflux (55 C.) for 29 hours, resulting in a yellowsolution with a trace of precipitate. Filtration removed 3.2 g. of awhite solid. Evaporation of the filtrate gave 72.4 g. of a pale yellowresidue. The residue was stirred with 61 ml. of water and filtered anddried to yield 22 g. of crude 'S-3-benz0[b]isothiuronium iodide, M.P.167-172 C. Recrystallization from 23/ 11% ethanol/H O solution andrinsing with ethyl acetate afforded a colorless analytical sample, M.P.173-174 C., which was characterized as follows:

IR, Am?

3300 cimr 3100 cm.- 161 0 cmr- 755 cm.- N.M.R. DMSO-dt TMS 4.85 (-CH S,singlet), 7.45 (H H-H multiplet), 7.86 (H singlet), 8.02 (H -+Hmultiplet), 9.09 (2NH broad singlet).

Analysis.Calcd for C H N S I (percent): C, 34.29; H, 3.16; N, 8.00; S,18.31; I, 36.24. Found (percent): C, 34.56, 34.58; H, 3.25, 3.14; N,8.16, 8.25; S, 17.42, 17.44; I, 37.44, 37.22.

EXAMPLE 6 Preparation of S-3-benzo[-b]thenyl isothiuronium acetate 3400cmr 1630 cmr 1550 cmr 760 cmr N.M.R.

1| 1.76 (011,00 singlet 4.60 (CH S, singlet), 7.96 (H -I-H multiplet),8.26 (2NH broad singlet), 7.75 (H singlet), 7.41 (HM-H multiplet).

Analyszls.-Calcd for C H N O S (percent): C, 51.04; H, 5.00; N, 9.93; S,22.71. Found (percent): C, 50.94; 50.94; H, 5.32, 5.21; N, 9.45, 9.51;S, 22.96, 22.96.

EXAMPLE 7 Preparation of S-3-benzo[b]thenyl isothiuronium benzoate To asolution of 0.87 g. (0.006 mole) of sodium benzoate in 7 ml. of water, asuspension of 1.0 g. (0.0039 mole) of S-3-benzo[b]thenyl isothiuroniumchloride in 10 m1. of absolute ethanol and 1.0 ml. of water at 50 C. wasadded. As a white precipitate was'formed immediately, an additional 20ml. of water was added. The resulting mixture was then heated at 65 C.for 10 minutes. Filtration yielded 1.47 g. yield) of a White solid, S-3-benzo[b] thenyl isothiuronium benzoate, M.P. 175-176 C.Recrystallization from ethanol yielded an analytical sample, M.P.166-168 C., which was characterized as follows: IR,

use

3200 cm.- (broad), 1590 cmr 1250 cmf 1150 cmr 755 cm.- ;N.M.R. Y

DMSO-dl TMS 11 4.78 (-CH S--, singlet), 6.80 (2NH broad singlet), twomultiplets centered at 7.45 and 7.90 for the aromatic protons.

Analysis.Calcd for C H N O' S (percent): C, 59.38; H, 4.68; N, 8.13; S,18.62. Found (percent): C, 56.33, 56.33; H, 4.49, 4.61; N, 8.49, 8.49;S, 19.51, 19.52.

EXAMPLE 8 Preparation of S-3-benzo [b] thenyl isothiuroniump-toluenesulfiriate A sample of 0.5 g. (0.028 mole) of sodiump-toluenesulfinate in 5.0 ml. of water was warmed on a water bath togive a clear solution. To this aqueous solution of sodiump-toluenesulfinate, a suspension of 1.0 g. (0.0039 mole) of S-3-benzo[b]thenyl isothiuronium chloride in 10 ml. of absolute ethanol and 1.0ml. of Water at 50 C. was added. The resulting mixture was heated at 65C. for 5-8 minutes. On cooling, 0.91 g. (63% yield) of a colorless,solid product, S-3-benzo [b]thenyl isothiuronium p-toluene sulfinate,was obtained. Recrystallization from an ethanol-water mixture affordedan analytical sample, M.P. 168-169 C., which was characterized asfollows:

use

3200 cm.- 1670 cm.- 750 chm- N.M.R.

'DMSO-ds TMS singlet), 4.70 (--CH S, singlet), 7.16

doublet), 7.42

and H +H doublet), 7.95 (HM-H multiplet), 9.90 (2NH broad singlet), 7.77(H singlet).

Analysis.Calcd for C H N O S (percent): C, 53.94; H, 4.80; N, 7.40; S,25.41. Found (percent): C, 52.61, 52.79; H, 5.15, 5.06; N, 7.08, 7.12;S, 24.39, 24.24.

EXAMPLE 9 Preparation of S-3-benzo[b] thenyl isothiuroniump-toluene-sulfonate water afforded an analytical sample, M.P. 170-172C.,

which was characterized as follows:

IR, A53 3260 cm. 1660 cmr' 1200 cmr 1030 cmr' 775 cmr' g N.M.R.

DMSO da TMS 2.2a -@-em singlet), 4.78 (-CH S-, singlet), 7.12

H cots-@1148 H 7.48 cmsm H H +H multiplet), 7.81 (H singlet), 7.98(H4+H7, multiplet), 9.17 (2NH broad singlet).

AH3lYSiS.-C31Cd for C17H13N303S3 (percent): C, 51.75; H, 4.60; N, 7.10;S, 24.35. Found (percent): C, 52.45, 52.33; H, 4.84, 4.83; N, 7.11,7.09; S, 24.53, 24.36.

The most outstanding property of the compounds of the present invention,and particularly the chloride, S-3-ben-zo [b]thenyl isothiuroniumchloride, is the highly selective abolition of aggressive behavior indoses which cause little or no signs or symtoms of central nervoussystem depression or toxicity. The compounds can be classified aspsychotherapeutic agents, but are unique in that no other agent of thisclass possesses the same spectrum of activity. The compounds of thepresent invention have neuropharmacological profi1es* in mice whichresemble those of the major tranquilizers such as chlorpromazine. Theydiffer from chlorprornazine, however, in that they are much weakerdepressants of motor activity in the mouse. The compounds of Examples10-16 of Table III below, in addition to having positiveneuropharmacological profiles, all gave protection in the isolatedfighting mouse assay. In particular, S-3-benzo{b]thenyl isothiuroniumchloride was very active in inhibiting aggressive behavior in threemodels of experimental aggression; namely, isolated fighting behavior inmice, electroshock-induced fighting in mice, and septal rat aggression.In a comparative study with a major tranquilizer, chlorpromazine, and aminor tranquilizer, chlordiazepoxide, the chloride of the presentinvention was found to be much more selective in inhibiting aggressivebehavior than the latter two agents. It does not possess significantanti-convulsant activity and in this respect it difiers fromchlordiazepoxide. It does, however, cause a significant hypothermia,which indicates an activity resembling chlorpromazine and other majortranquilizers. It is a weak potentiator of pentobarbital and is inactivein the dl-dopa fighting test for monamine oxidase inhibitors. Itapparently does not possess anti-depressant activity since it did notreverse tetrabenazine ptosis. The chloride of the present invention isorally active in mice and rats and orally is less toxic thanchlorpromazine and chlordiazepoxide. By contrast with the chloride ofthe present invention, S 3 benzo [b]thenyl isothiuronium chloride, its2-isomer, S-2-benzo{b]thenyl isothiuronium chloride doublet) had noactivity as an antiaggression drug.

Table III lists, in addition to compounds of the present invention(Examples 10-16), fourteen related compounds, including the 2-isomer ofthe chloride (Example 29);

*The neuropharmacologlcal profile is a standard procedure (see, e.g.Samuel Irwin, Science, 186, 123 [1962]) employed in screening a compoundto determine its usefulness as a central nervous system active compound.When a compound is found to have sufficient activity to warrantfollow-up, the grstnuiaggression screen, the fighting mouse assay, is deermine 13 which were tested for similar activity but with negativeresults.

14 Similar observations were noticed after oral administration of thiscompound, except that no convulsion were TABLE III Neuropharmacologicalprofile R l i Pharmacologi- Example No. n R R cal profile 10 NHQ HCHa-S-C\ 01 11 NHz H 'i' CHz-S-C Br 12 NEW H om-s-o ooo 13- NHEQ HCHz-S-C\ I 14. NHfi H -orn-s-o H3c-s 02 15 NHz H -om-s-o mc-Q-s 16 NHz HCH2-S-C CHsCOO NH: H C 0 OEt CHzCl H CHsOHtCOOH H CHz-CHECOOEt): HOHz-CH 00011) H H CHgOH (Hypnotic)+ -0 Et H CHz-S-Ph H H201 H H S OzPhpMe) H CHaC 30H.

N H CHz-S 29. H NH (Hypn0tic)+ CHr-S-C C1 NH: 30 CHz-SH H NOTE:+=Indicates active; =Indicates inactive; +=Indicates weakly active.

Example 23 is the 2: 3-dihydr0 derivative. Example 29 is the2-benzo[b]chloride isomer, which showed some CNS depressant activity inthe neuropharmacological profile with mild hypnotic activity. In furtherhypnotic assays this compound proved inactive and, more important, wasinactive in the isolated fighting mouse and the septal rat tests. Bycontrast, its 3-isomer (the chloride of the present invention [Examplewas very active in the latter two tests, which are diagnostic tests forantiaggression activity.

In the neuropharmacological profile, which is a standardizedmultidimensional observation technique used on mice to gradesymptomatology and acute toxicity relative to dosage, theS-3-benzo[b]theny1 isothiuronium chloride compound of the presentinvention caused convulsions and/or death after intraperitoneal doses of300 and 100 mg./kg. After doses of 30, 10, and 3 mg./kg., depression,hypothermia, hypo-and hyper-reflexia, reduced motor activity, and somedegree of catatonia were observed. Depending upon the dose used, theonset of action varied from 4 to 30 minutes.

observed at the 300 mg./kg. dose. In addition, the onset of action waslonger, ranging from to 60 minutes. These observations indicate a lesserdegree of absorption following oral administration as compared tointraperitoneal dosing.

S-3-benzo[b]thenyl isothiuronium chloride and two commonly usedtranquilizers were subjected to the spontaneous locomotor activity test,in which six mice or rats per dose were placed in individual photocellactivity cages minutes (mice) or minutes (rats) after I.p.(intraperitoneal) administration of the drug for a 30 minute activitycount. Table IV shows the results obtained by comparing drug-treatedgroups with control activity, the SD being that dose causing a 50%reduction from control activity.

The time of peak effect for each agent in both species was 15-30 minutesafter drug administration.

Again, S-3-benzo [b]thenyl isothiuronium chloride was less potent thaneither reference drug. In addition, S-3- TABLE Iv 5 benzo[b]thenylisothiuronium chloride appeared to be spontanmuslommom activity morecentrally toxlc 111 rats than in mice.

This compound was also compared with chlorproma- LP. D50 e/ 8 zinc andchlordiazepoxide for its anti-aggressive activity. Mice Rats Four modelsof experimentally-induced aggression in s a benmlblmenyusotmmmumchloride 2L5 4Z5 10 rodents were studied (R. D. Sofia, Life Sciences 8:705, Chlorpromazine 2.8 1.7 1969). The results of these experiments aresummarized Chlor p 12.8 14.0 in Table VL The results of this studyindicate that the S-3-benzo [b]- 's ig g g g g g f' g i 3 thenylisothiuronium chloride compound of the present 3: g i: 0 i f inventionpossesses selective anti-aggressive activity against I g ig i p i ne .5isolation-induced aggression and septal rat aggression, i g ffi g ifi 'fg which no standard psychotherapeutic agent possesses. In 9 any uromumce comparison with chlorpromazine and chlordiazepoxide, exhibiteddepressant activity when given orally, Wllh an using the ratio betweenNTDEU and ED in these m0 d e15, ig g f f m mice and greater than 200 29S-3-benzo[b]thenyl isothinronium chloride possesses a high degree ofspecificity in combating experimentallyg g mumtoxlcltty test E g fi ginduced aggressive behavior. Drug specificity on these i Sag d mlce 1studies was considered selective only when it occurred at g i g i f' g'mdoses which were significantly lower than those which ime P e l r o S npaired rotarod performance (NTD or resulted in a motor function orcentral nervous system toxicity. The ratio (NTDEOIEDEO) of greater than1 0 z g F m Tllble as: fif Electroshock-induced fighting is a testprocedure that 3 y fi g gp g 35 was s e agams c selectively depictsanti-anxiety activity. This fact was Pr mazm a c I la po 1 shown sincechlordiazepoxide was quite active.

TABLE 30 Killer rat aggression appears to be a test which selec- Micatively indicates anti-depressant and stimulant activity since referenceagents from both these classes of drugs are gf gff $239332; selectivelyactive (R. D. Sofia, Life Sciences, 8: 120, P l 1969). None of the drugstested selectlvely mhibited killer 's-a-bemommeu usotmurimum ratbehavior.

fiig g g 153. (1106-205)? Chlorpromazme was able to block all types ofaggres- Chlordiazepoxide I 13:8 7. '1-27I o; sive behavior, but onlyafter doses which caused neurog i r 33 0 (47 H46) toxicity, which isexpected of this major tranquilizer.

' Hence, S-3-benzo[b1thenyl isothiuronium chloride differs from bothchlorpromazine and chlordiazepoxide in ,1 that it selectively inhibitsseptal rat aggression and isoiifig m 35 5 (23 1) lated mouse aggressionat doses well below those causing ch10lpl01I 12;1 .l I;::: '1. 1;?'1.02Is) signs of neurotoxicity. In addition, this degree of selecfg giigggfi fikfi aa w-"" tivity of S-3-benZo[b]thenyl isothiuronium chloridefor chloride- 300.0 antiaggressive activity is further supported by thefact that irntraperitoneal. it is quite active at doses well below dosesinhibiting oral (Per spontaneous locomotor activity.

TABLE VL-ANTI-AGGRESSIVE ACTIVITY [ED confidence limits) (mg./kg.)]

I.p. P.o.

N'IDso/ m/ Agent E1350 E1350 E1350 EDso Isolated mouse aggression(sz-gibenzolbkhfnylisothluronium chloride 8- (g-(i 2 )g 1?.(7) u 1 D. ggfifitfiifigtlifi. 20.5 11. 3-315) 0.1 35.0(25.4-4s.3) 1.5

Electroshock-induced fighting in mice sdgibenzolbltliixenylisothiuronium chloride- 5 3 H .-..6. -.6;E6. i "LE6 em lhtfisia::::::::::::::::::::::.--- 412 213-717) s3 sum-ail 18.0

Septal rat aggression %-%-lbenzo[b]thenyl isothiur ninmehlorlde176(;((3; g-lfs 114.428.1351. (1)) 7%?) om8l$3t1i 25.5; 14104715) 0Z423.5(1310-5910) 0.49

7 Killer rat aggression ggibenzolmthenylisothiuronium 0hloxide..47.0522. unfilziaiaaas "6.6

no em i iiifififihden. 36 Mata/154.4) 0.3 74.0(53.1-102.s) 0.15

1 Weekly active.

17 Anticonvulsant activity was tested in the following procedures.

( 1) Maximal electroshock seizures (MES In this study, groups of tenmice each are injected i.p. (intraperitoneally) with vehicle and testdrug and placed in individual Plexiglas squares. Thirty minutes afteri.p. injection each mouse is administered an electric shocktranscorneally at 50 ma. intensity, 0.2 second duration (Swinyard, etal., J. Pharmacol. Exptl. 106: 319, 1952). The criterion for activity isprotection against tonic extension of the hind limbs. The dose necessaryto protect 50% of the mice (MES was determined. The following resultswere obtained:

TABLE VII Maximal electroshock seizures Agent: LP. MES mg./kg.

S 3-benzo[b]thenyl isothiuronium chloride 125 chlorpromazine Inactive(25 mg./kg.). Chlordiazepoxide 41.5 (37.8-45.6).

S 3-benzo [b]thenyl isothiuronium chloride is much less potent thanchlordiazepoxide in protecting against MES but dilfers fromchlorpromazine in that the latter is completely devoid of actiivty.

(2) Pentylenetetrazol seizures (MET Pentylenetetrazol seizures Agent:I.P. MET mg./kg.

S-3-benzo[b]thenyl isothiuronium chloride Inactive (100 mg./kg.).chlorpromazine Inactive (100 mg./kg.).

7.1 (5.6-90) for convulsions. Chlmdlazepmde {2.6 2.2-3.1 for death.

Of the drugs tested, only chlordiazepoxide exhibitedanti-pentylenetetrazol activity.

d-Amphetamine aggregation Protection from d-amphetamineaggregation-induced lethality is usually afiorded byalpha-adrenergic-blocking agents such as chlorpromazine,penoxybenzamine, etc. Percent protection was determined for eachcompound and ED value calculated. The results are summarized in TableIX.

TABLE XI d-Amphetamine aggregation Agent: ED ing/kg.

S-3-benzo[b]thenyl isothiuronium chloride 50 mg./kg. Chlorpromazine 1.2(0.8-1.8) mg./kg. Chlordiazepoxide Inactive (50 mg./kg.).

In this test procedure, S-3-benzo[b]thenyl isothiuronium chloride hasapproximately V the potency of chlorpromazine, while chlordiazepoxide iscompletely inactive. Therefore, the chloride of the present inventioncan be considered to possess very weak alpha-adrenergic blockingactivity.

Drug interaction studies S-3-benzo[b]thenyl isothiuronium chloride,chlorpromazine, and chloridazepoxide were administered at various lowingdrug interaction studies.

( 1) Pentobarbital S-3-benzo[b]thenyl isothiuronium chloride,chlorpromazine, and chlordiazepoxide were administered at viarous dosesintraperitoneally 30 minutes prior to 50 mg./kg. i.p. injection ofsodium pentobarbital. This procedure detects compounds which possessanaleptic or potentiating properties. The duration of sleeping time, asmeasured by loss of righting reflex, was determined. The results arepresented as percent of control sleeping time and are shown in Table X.

TABLE X.-PEROENT IhiffigASE IN CONTROL SLEEP thenyl iso- Chlor- Chlor-I.p. dose, thiuronium promdiazmgJkg. chloride azine epoxide On a dose todose relationship, S-3-benzo[b]thenyl isothiuronium chloride appears tohave approximately the potency of chlorpromazine. That is, it requiresabout 20 times as much as S-3-benzo[b]thenyl isothiuronium chloride asof chlorpromazine to achieve the same potency. On the other hand, at thesame dosage, 10 mg./kg., S-3-benzo[b]thenyl isothiuronium chloride hasapproximately two to three time more potency than chlordiazepoxide.Therefore, this compound of the present invention shows potentiation ofbarbiturate anesthesia.

(2) Dihydroxyphenylalanine (dl-DOPA) fighting test It is well known thatwhen monamine oxidane (MAO) inhibitors are given prior to thenoradrenaline precursor, dl-DOPA, convulsions or excitation occur. Inthis study, the MAO inhibitor, pargyline, mg./kg.) was given 1, 2, and 4hours prior to administering 200 mg./kg. of dl-DOPA. Results of thisexperiment are manifested by excitation, salivation, jumping, andfighting. When S-3- benzo[b]thenyl isothiuronium chloride (60 mg./kg.),chlorpromazine (5 mg./kg.), or chlordiazepoxide (15 mg./kg.) wereadministered instead of pargyline, these symptoms were not observed.Thus, in this procedure, none of the agents tested appear to be MAOinhibitors.

(3) Yohimbine potentiation Potentiation of lethality induced by thealpha-adrenerinvestigators as a reliable procedure to classify possibleantidepressant compounds (R. M. Quinton, Brit. J. Pharmacol., 21: 51,1963). An ED in this test is defined as that dose of test drug-whichwill cause the LD (25 mg./ kg. i.p.) of yohimbine to be converted totheLD value. Groups of ten mice each are placed in a tote box and areinjected with vehicle or test drug. Thirty minutes later each mouse isinjected i.p. with yohimbine at 25 mg./kg. Sixty minutes followingyohimbine administration, the number of deaths in each tote box for eachdose of test drug is recorded. (Vehicle-treated mice should have none orone of ten mice dead.) Neither chlorpromazine (10 mg./kg.) norchlordiazepoxide (20 mg./kg.) was active in this test. However,S-3benzo[b]thenyl isothiuronium chloride resulted in an ED value of 54.2mg./kg. (29.2- 101.5). Since S-3-benzo[b]thenyl isothiuronium chloridewas not selectively active in the killer rat aggression test, whichappears to detect antidepressant activity, it is possible that thisagent migh possess weak antidepressant activity at doses which causeneurotoxicity. Hence, a

third test for detection of antidepressant activity was conducted.

(4) Antagonism of tetrabenazine-induced ptosis Groups of mice were given32 mg./kg. of tetrabenazine or suspension thereof in a suitable solventor suspension medium.

The compounds and compositions of the present invention may also beadministered rectally in the form of a suppository comprising anetfective amount of the deintraperitoneauy 30 minutfis after aninleiltion of 5 sired compound and a suitable vehicle such as petroleumbenzo[b]thenyl isothiuronium chloride (30 mg./kg.). je11y The degree ofPtosis (eyelid drooping or closure) was The following examples arespecific formulations of then determined exactly 30 minutes aftertetrabenazine compositions in accordance with the inventionadministration. S-3-benzo[b]thenyl isothiuronium chlon'de did notreverse tetrabenazine-induced ptosis as do EXAMPLE 31 theantidepressants desipramine and amltriptyline. Tablets may ba preparedby the compression of a wet (5) Oxotremorine antagonism granulationcontaining the following:

Antagonism of the pharmacological effects of oxotre- F Ingredients: Ineach morine, a potent cholinergic stimulant, was studied in S 3benzo[b]thenyl isothiuronium chlomice after intraperitonealadministration of S-3-benz0 [b] ride mg 5 thenyl isothiuronium chloride(100 mg./kg.). (F. Sjoquist Polyvinylpyrrolidone mg 6 and J. Gillette,Life. Sci., 4: 1031, 1965). In this test, Lactose mg 25 groups of tenmice are individually placed into Plexiglas Alcohol, 3A, 200 proof ml 1squares. Mice are injected i.p. with the vehicle or test Stearic acid mg3 drug thirty'minutes prior to an i.p. injection of oxotrem- Talc mg 4orine at 0.5 rug/kg. Immediately following oxotremo- C t r h mg 15 rineadministration, the mice are observed for salivation D 1 t bl t 3 d andtremors. Peripheral anticholinergic activity is assessed Osage a e a byinhibition of salivation, and central activity by inhib- EXAMPLE 32ition of tremors. At 100 mg./kg., S-3-benzo[b]thenyl isothiuroniumchloride was completely devoid of any anti- A liquid suspension for oraladministration may be cholinergic activity. prepared in the followingformulation:

1 (6) Lethality study Ingredients: each 5 cc.

Table XI gives the results of five-day lethality studies g' g g g f fi ichloride 2 following single injections of a drug. All values presentedgi oxyme cc u 056 represent tests conducted when animals were housed tenSyrup to per cage. S-3-benzo[b]thenyl isothiuronium chloride is Dosage:1 teaspoonful (5 cc.) every 3 to 4 hours. compared with chlorpromazineand chlordiazepoxide. In EXAMPLE 33 these and all the precedingcalculations, the method of Litchfield and Wilcoxon (J. Pharmacol.Exptl. Ther. 96: Dry fill d capsules consisting f two sections 99, 1949)was used to estimate the effective (ED or of hard gelatin may beprepared from the following lethal (LDso) dose. formulation:

TABLE XI [LDsn (95% confidence limits) mg.lkg.]

Mice Rats Agent I.p. P.o. I.p. P.0.

S-3-benzolblthenyl isothiuronium chloride 685 (413-1, 090) 1, s10(em-1,765) 67.5 (53. 1-75. 7) s90 (58l1,356) Chlorpromazine 136(106-174) 280 (187418) 137 (133-141) 357.7 (237. 7-538. 5)Chlordiazepoxida 400 (265-604) 810 (ass-95s) 205 (224-313) 302.1(235.5-753.5)

These data show that S-3-benzo [bjthenyl isothiuronium Ingredients: Ineach chloride is much less toxic in mice than in rats when administeredintraperitoneally and that it is much less toxic for both methods ofadministration in mice and when orally administered to rats whencompared to the two standard reference drugs.

The compounds of the present invention, either alone or in the form of apharmaceutical composition, may be administered to an animal subject inany of a number of forms and via any of several routes. Thus, thecompounds or compositions thereof may be orally administered in the formof tablets, pills, capsules or in the form of a solution or liquidsuspension. They may also be administered in the form of a parenteralsuspension or solution. The compounds or compositions thereof may alsobe administered rectally, in the form of a suppository.

When orally administering the compounds or compositions, use can be madeof a tablet, pill or capsule consisting entirely of the desiredcompound, although ordinarily, a composition comprising an effectiveamount of the compound and varying amounts of one or morephysiologically inert materials such as carriers, vehicles, binders andthe like will be used. Additionally, the compounds may be orallyadministered in the form of a suspension thereof in a suitable vehiclesuch as a syrup.

When parenterally administering the compounds or compositions, use maybe made of a parenteral solution S-S-benzo [bJthenyl isothiuroniumchloride mg 5 Lactose USP, q.s.

Dosage: 1 capsule three times a day.

EXAMPLE 34 A parenteral suspension for intramuscular administration maybe prepared in the following formulation:

EXAMPLE 35 A suppository capsule may be formulated as below:

Ingredients: In each S-3-benzo[b]thenyl isothiuronium chloride ..mg 5Cocoa butter, q.s.

Dosage: 1 suppository every 3 to 4 hours.

Variations can, of course, be made without departing from the spirit andscope of the invention.

Having thus described our invention, what we desire to claim and protectby Letters Patent is:

21 22 1. A compound selected from the group consisting of OTHERREFERENCES the base, 2-(3-benzo[b]thenyl)-2-thiopseudourea, and theCagniant, R" Acad Sci" Sen C 1970, 271 (17),

benzoate, p-toluenesu1finate, p-toluenesulfonate and ace- 10364089 (Oct28 1970) tate of said base.

ti'lu ifiislffi iihfifieihf mi? riiiiitl 5 ALAN ROTMAN Primary Examinerp p e C. M. S. JAISLE, Assistant Examiner base.

References Cited US Cl XR UNITED STATES PATENTS 424 27s 3,186,990Lambrech et a1 260-251 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3,79 Baud Feb. 5, 1974 unmet-(8) Zawen S. .Ariyanand Shih-Yu Me It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 1, line 50: That portion 9;? pile formula. reading -CH NSi-Cshould read CH -s-c 2 Column 5, line 71: "hydrous" should read"anhydrous".

Column 12, lines 611E632 Thaf portion of the formula.

reading should read Ll U Column 21 line 5: c:oznpoud.'.' should read-compound--.

Signed and sealed this 1st day of October 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner ofPatents

